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目的探讨脊髓小脑共济失调2型(SCA2)致病基因ATXN2异常等位基因中间重复个体的表型和分子遗传学特点。方法针对2005—2018年中日友好医院神经科运动障碍与神经遗传病研究中心收集的1383个常染色体显性遗传共济失调家系的先证者和部分家系成员,采用荧光标记毛细管电泳片段分析方法进行动态突变检测,对携带ATXN2基因中间重复的个体进行临床表型和遗传特征分析。结果共检出163个家系(包含先证者和家系成员共203人)携带异常扩展的ATXN2基因CAG重复序列,其中93个家系中有107例的异常扩展等位基因重复次数在29~34次之间。在其中的20个亲子对中,父系遗传16个,异常等位基因的代间扩展增加0~28次,母系遗传4个,异常等位基因的代间扩展增加0~4次。结论对于临床拟诊SCA2家系患者,需对其亲代或成年子代个体进行ATXN2基因检测,以免漏诊。动态突变基因检测有助于识别中间重复的个体,对明确家系致病基因和遗传咨询至关重要。  相似文献   
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【摘要】 目的 检测一个常染色体隐性遗传性羊毛状发家系的致病基因。方法 收集1个中国汉族常染色体隐性遗传性羊毛状发家系2例患者及其他家族成员的临床资料,采集他们的外周血和100例健康人外周血,提取DNA。应用二代皮肤靶向测序包检测患者的基因突变,然后采用Sanger测序验证,对突变基因编码蛋白质进行功能预测。结果 2例患者均在LIPH基因存在错义突变c.530T>G(p.Leu177Arg)和c.736T>A(p.Cys246Ser),这2个突变分别来自患者父母,而100例健康对照中均未发现此两种突变。物种间序列比对分析发现,LIPH基因所编码蛋白质第177位亮氨酸和第246位半胱氨酸均属于高度保守的序列,SIFT和Polyphen?2软件预测c.530T>G(p.Leu177Arg)和c.736T>A(p.Cys246Ser)突变均为有害变异位点。结论 LIPH基因的错义突变c.530T>G(p.Leu177Arg)和c.736T>A(p.Cys246Ser)可能为引起该家系羊毛状发患者临床表型的致病基因。  相似文献   
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Introduction and objectivesOur objective was to approximate the prevalence of mutations in candidate genes for familial hypercholesterolemia (FH) in a middle-aged Spanish population and to establish the predictive value of criteria for clinical suspicion in the detection of causative mutations.MethodsUnrelated individuals aged ≥ 18 years from the Aragon Workers’ Health Study (AWHS) with high low-density lipoprotein cholesterol (LDL-C) and clinical suspicion of FH (participants with LDL-C concentrations above the 95th percentile, participants with premature cardiovascular disease and/or participants with high LDL-C [130 mg/dL] under statin therapy), assuming that any participant with FH exhibits at leats 1 trait, were selected and the LDLR, APOB, PCSK9, APOE, STAP1 and LDLRAP1 genes were sequenced by next generation sequencing technology.ResultsOf 5400 individuals from the AWHS, 4514 had complete data on lipid levels and lipid-lowering drugs, 255 participants (5.65%) met the criteria for suspicion of FH, 24 of them (9.41%) were diagnosed with hyperlipoproteinemia(a), and 16 (6.27% of those sequenced) were found to carry causative mutations in candidate genes: 12 participants carried 11 different pathogenic LDLR alleles and 4 participants carried 1 pathogenic mutation in PCSK9. LDL-C concentrations > 220 mg/dL and LDL-C > 130 mg/dL despite statin therapy showed the strongest association with the presence of mutations (P = .011).ConclusionsOur results show that the prevalence of FH in Spain is 1:282 and suggest that the combination of high untreated LDL-C and high levels of LDL-C despite statin therapy are the best predictors of a positive FH genetic test.  相似文献   
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目的分析并比较18F-脱氧葡萄糖(FDG)PET及CT影像组学参数在预测肺腺癌患者表皮生长因子受体(EGFR)表达中的作用。方法回顾性收集2017年1月至12月间于南方医院就诊的114例[男64例,女50例,年龄35~84(平均61)岁]肺腺癌初治患者的治疗前18F-FDG PET/CT图像及其EGFR表达资料。用LIFEx软件手动逐层勾画感兴趣体积并提取图像参数,通过最小绝对收缩和选择算子(LASSO)方法重复200次进行参数选择,经十倍交叉验证选择模型的最优调和参数λ,再采用logistics逐步回归进一步筛选参数建模。针对3种数据集(PET参数、CT参数、PET+CT参数)构建3种模型,分别记为MPET、MCT、MPET+CT。用受试者工作特征(ROC)曲线分析模型预测EGFR突变的价值,获得曲线下面积(AUC)、灵敏度、特异性、准确性,采用Delong检验比较三者的AUC。结果114例肺腺癌患者中,EGFR野生型61例(53.51%),EGFR突变型53例(46.49%)。最终从PET、CT、PET+CT图像参数中分别筛选出3、3、7个参数构成回归模型MPET、MCT、MPET+CT,三者AUC分别为0.730、0.752、0.866。当三者界值分别取0.427、0.522、0.378时,约登指数最大,分别为0.420、0.405、0.630,灵敏度分别为83.0%(44/53)、58.5%(31/53)、92.5%(49/53),特异性分别为59.0%(36/61)、82.0%(50/61)、70.5%(43/61),准确性分别为70.2%(80/114)、71.1%(81/114)、80.7%(92/114)。MPET与MCT的AUC之间差异无统计学意义(z=-0.320,P>0.05),MPET+CT与MPET、MCT之间AUC差异均有统计学意义(z值:2.963、2.523,均P<0.05)。结论PET、CT、PET+CT影像组学均与肺腺癌EGFR基因表达状态相关,其中MPET+CT预测效能最高。  相似文献   
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子宫内膜癌近年发病呈上升趋势且发病年龄不断年轻化,晚期子宫内膜癌治疗效果不理想。传统的分类方法在患者的诊疗中存在严重的不足,不能为患者精准治疗提供足够的依据。随着分子生物学的快速发展,越来越多的研究发现子宫内膜癌发病的多组学研究和信号通路关联,临床上迫切需要将其纳入患者的常规诊疗中。传统分型根据有无雌激素刺激将子宫内膜癌分成Ⅰ、Ⅱ两型,Ⅰ型子宫内膜癌的诊断和预后与人第10号染色体缺失的磷酸酶及张力蛋白同源的基因(PTEN)、磷脂酰肌醇3激酶基因(PI3KCA)、磷酸肌醇3激酶调节亚单位1(PI3KR1)、AT丰富结合域1A(ARID1A)、Kristen鼠肉瘤病毒原癌基因同源体(KRAS)、POLE、CTNNB1、TP53突变,DNA错配修复(MMR)蛋白缺失,雌激素受体(ER)、孕激素受体(PR)表达情况有关。Ⅱ型子宫内膜癌的预后与人表皮生长因子受体2(HER2)过表达、TP53突变、ARID1A突变有关。磷脂酰肌醇3激酶/蛋白激酶B(PI3K/Akt)、P53、丝裂原活化蛋白激酶(MAPK)和Wnt/β-连环蛋白信号通路与子宫内膜癌的发病密切相关。TCGA分型的替代分子分型ProMisE和Parra-Herran分子分型目前被临床用以评估子宫内膜癌的预后与治疗方案,但该分型与预后仍存在部分不匹配的病例,需要对该分型进行进一步细化研究。  相似文献   
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Cobalamin (cbl) C disease is a rare autosomal recessive inheritance disease, which is the most common cobalamin metabolic disorder. Its clinical phenotype involves multiple systems with varying degrees of severity, where in mild cases can be asymptomatic for many years, whereas severe cases may cause death during the neonatal period. The disease is caused by mutations in the MMACHC gene located on chromosome 1p34.1 that contains 5 exons; among which, exons 1–4 have an 849 bp coding sequence that encodes a protein containing 282 amino acids. Through clinical physical examination and laboratory tests, especially blood and urine screening, we found 28 cblC pediatric patients with clinical manifestations, such as mental retardation, motor development delay, epilepsy, metabolic acidosis, vomiting and diarrhea. By Sanger sequencing, we found homozygous or compound heterozygous mutations of MMACHC in 27 of the patients, and single heterozygous mutation of MMACHC in one of them. The c.609G > A, c.658-660delAAG, c.80A > G and c.482G > A mutations accounted for 43.64% (24/55), 10.91% (6/55), 9.09% (5/55) and 7.27% (4/55) of all the mutations, respectively. This spectrum finding is basically consistent with the previously reported data in Chinese patients. The most common c.609G > A mutation may likely lead to early-onset cblC disease. In previous literature involving a large sample of Caucasian cblC cases, the mutation spectrum of MMACHC gene is almost completely different from that of the Chinese population. The most common mutations in the Caucasian population were c.271dupA, c.394C > T and c.331C > T, which account for 48.05% (542/1128), 13.65% (154/1128) and 7.36% (83/1128) of all the mutant alleles, respectively. The c.271dupA mutation and c.331C > T mutation were mainly associated with early-onset cblC in children less than 1 year old, whilst the c.394C > T mutation was mainly associated with late-onset cblC patients characterised by isolated acute nervous system abnormalities. We also analysed the cause behind the different mutation spectrum of MMACHC gene between the Chinese and Caucasian populations.  相似文献   
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Background

Programmed death ligand-1 (PD-L1) is a potential predictive biomarker for immunotherapy in several malignancies. However, the expression level and clinical significance of PD-L1 in von Hippel–Lindau (VHL)-associated hereditary clear-cell renal cell carcinoma (ccRCC) remain unclear.

Patients and Methods

Surgical specimens were recruited from 129 patients with sporadic ccRCC and 26 patients with VHL-associated hereditary ccRCC. The PD-L1 expression level was assessed using immunohistochemistry. Correlations between PD-L1 expression and clinicopathological features were analyzed.

Results

In sporadic ccRCC, the positive expression rate of PD-L1 was 47.3% (61/129). Positive PD-L1 expression was correlated with advanced tumor T stage (P = .011), higher Fuhrman nuclear grade (P = .022), poor disease-free survival (P = .037), and sex (P = .025). In the VHL-associated hereditary ccRCC, positive PD-L1 expression rate was 34.6% (9/26), lower than that in sporadic ccRCC. Positive PD-L1 was correlated with higher Fuhrman nuclear grade (P = .008), but not with sex, age, tumor stage, or the onset age of VHL-associated tumors.

Conclusion

Positive PD-L1 expression was correlated with the aggressive clinicopathological features in sporadic and VHL-associated hereditary ccRCC. Whether PD-L1 expression level in ccRCC is related to the effectiveness of programmed death-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated.  相似文献   
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